There may still be much unknown about the production process of Advanced Glycation End-products (hereinafter referred to as AGE). However, it is thought that the key factor of AGE is a non-enzymatic glycation. In other words, it is thought that in the initial-stage reaction of AGE production, an amino group that exists in protein and an aldehyde group which is a reducing sugar such as glucose or the like, non-enzymatically react to each other (i.e. glycation), which produces Amadori-rearrangement products through Schiff's base. In the late-stage reaction, AGE is produced after a long period of complex cleavages and condensations.
Diabetes complication includes retinopathy, nephropathia, neuropathy, ischemic cardiac disease, cerebrovascular disease and others. It is known that one of the factors for the cause of these diseases relates to AGE produced in a hyperglycemic biological body. (For instance, refer to non-patent reference 1)
Diabetic nephropathy is renal microvascular damage caused by diabetes. Its basic pathological change includes the thickening of the glomerular basement membrane and the expansion of the mesangial area. Recently a number of diabetic patients stricken with the end-stage renal disease, caused by diabetic nephropathy increases and so were treated with dialysis. It is thought that AGE which is produced by a continuous state of hyperglycemia is involved in the development of nephropathy which is developed by 1. enhanced vascular permeability, 2. enhanced deposition of protein and lipoprotein, 3. inactivation of nitric oxide (NO), and 4. accelerated production of extracellular matrix. (See Non-patent Reference 2.)
For the sake of the prevention of and for the improvement of diabetic complications, various types of AGE production inhibitors have been researched and developed.
For example, it is shown that AGE production that induces diabetic complications such as nephropathia, retinopathy and others is inhibited by synthetic drugs (synthetic compounds). (See Patent References 1 and 2.) However, such synthetic drugs [that inhibit such] AGE production remains in the developmental stage, and such synthetic drugs often produce unanticipated side effects.
Contrarily, research is being done of substances or food compositions which prevent, control, improve and cure diseases through a daily dietary way of life, instead of using synthetic drugs. Patent References 3 to 5, for instance, show compositions of extracts of plants used for food, which inhibit AGE production.
However, AGE inhibitory activity of such extracts derived from plants is generally very low, compared to that of synthetic drugs (synthetic compounds), and the amount of the extracted active substance is extremely small.
To prevent or cure diabetic complications, continuous and long-term therapy is required. Thus, it is desired to develop an AGE production inhibitor that both effectively inhibits AGE production and avoids side effects. However, little is known about conventional botanical extracts which meet public expectation.
In recent years, it has been disclosed that AGE relates closely not only to diabetes but also to the aging of the skin. AGE increases with aging, and when Maillard reaction occurs in the collagen part [of the skin] which is the skin protein, the carbonyl group of glucide, non-enzymatically reacts with either the amino group of lysine residue or with the guanidyl group or arginine group in the protein to produce AGE, thus resulting in collagen cross-linking. Once the link structure is formed, the molecule is hardened, and inherent elasticity of the skin is lost. Also, such crosslink substances are treated as foreign substances, and the volume of secretion of degrading enzyme (collagenase, elastase) increases, which decreases skin tone and firmness and weakens the skin, thus resulting in wrinkles, slackness and dullness of the skin.
As such, AGE is now recognized as a trigger of diabetes complications. From the viewpoint of anti-aging care, the production mechanism of AGE is also focused.